immuno pharmacology of transplantation n.
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Immuno -pharmacology of Transplantation. Important Points to Note ​ --T cell response is responsible for organ rejection ​--Inhibition of CD4 T cell activation is a major strategy to prevent rejection ​--Calcineurin is the major signal transducer of calcium signaling in T cells

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slide2

Important Points to Note

  • ​--T cell response is responsible for organ rejection
  • ​--Inhibition of CD4 T cell activation is a major strategy to prevent rejection
  • ​--Calcineurin is the major signal transducer of calcium signaling in T cells
  • ​--CsA, FK506, and Rapamycin bring two proteins together to block a third protein
slide3

Immunosuppressant Drugs focus on CD4 T Cells

  • Inhibitors of MHC-peptide-T cell receptor interaction T cell activation requires the T cell receptor (TCR) to recognize the MHC-peptide complex.
  • --Antithymocyte Globulin is produced in animals and is used to prevent acute rejections.
  • ​Major side effects include serum sickness and nephritis from host reaction to animal proteins.
slide4

--Anti-CD3 antibodies (Orthoclone) prevents TCR binding to MHC-peptide complex, but also ​depletes T cell population.

  • ​Side effects include “cytokine release syndrome” which is basically flu symptoms with ​the risk of shock.
slide5

Inhibitors of TCR-mediated intracellular signaling

  • --Cyclosporine (CsA) is a fungal metabolite that works very similar to FK506. It is sequestered ​in RBC, which act as a reservoir.
slide6

It is extensively metabolized in the liver by Phase I ​enzymes.

  • Main toxicity is nephrotoxicity.
  • --FK506 (Tacrolimus) has the same mechanism of action and toxicity as CsA. These drugs are ​very similar in all respects.
slide7

Mechanism of action of Cyclosporine (CsA) and FK506 is very unique. They don’t bind target enzyme directly, ​but must complex with an intermediate cellular protein. Both drugs bind immunophilin, ​and the drug-immunophilin complex is the inhibitor.

slide8

CsAbinds an immunophilin called cyclophilin.

  • The corresponding protein for FK506 is FKBP. ​The drug-protein complex is not sufficient for T cell inhibition. It must block calcineurin.
slide9

Calcineurin is a protein phosphatase that transduces calcium signals from the cytosol to the ​nucleus via a transcription factor called NFAT.

  • Calcium signals occur when MHCII-​peptide complexes bind the TCR.
  • Activated calcineurin dephosphorylates NFAT, which ​goes to nucleus and binds enhancer regions to turn on cytokine transcription.
slide10

Since CsA-​cyclophilin and FK506-FKBP complexes inhibit calcineurin, NFAT remains quiescent.

  • ​The binding of MHCII to the TCR doesn’t result in cytokine up regulation, and the T cell ​stays quiet
slide11

Inhibitors of cytokine action:

  • One of the most important CD4 T cell cytokines is IL2.
  • IL2 is secreted by T cells but also binds ​receptors on the T cell surface, causing auto-stimulation and proliferation. Monoclonal ​antibodies against these receptors block T cell proliferation.
slide12

Inhibitors of cytokine receptor mediated signal transduction

  • --Rapamycin blocks a different signal cascade than FK506, although it is structurally similar ​and also works through FKBP.
  • Rapamycin blocks IL2-dependent T cell proliferation, but ​not by inhibiting calcineurin.
slide13

Instead, the Rapamycin-FKBP complex binds TOR, which ​regulates transcription/translation of genes required for T cell activation.

  • ​Rapamycin is synergistic with CsA and FK506.
slide14

Rapamycin induces T cell tolerance to the graft, so you may be able to eventually stop the drug. ​With CsA and FK506 you block T cell activation but also proliferation, which prevents ​the development of tolerance to the graft and requires lifetime use of the drugs.

slide15

Inhibitors of T cell proliferation

  • --Mycophenolate Mofetil is a prodrug of mycophenolic acid, which inhibits purine synthesis.
  • ​Since T and B cells both require de novo purine synthesis, they are selectively targeted.